Increased Intratumoral Neutrophil in Colorectal Carcinomas Correlates Closely with Malignant Phenotype and Predicts Patients' Adverse Prognosis

Background Substantial evidence suggests that the presence of inflammatory cells plays a critical role in the development and/or progression of human tumors. Neutrophils are the common inflammatory cells in tumors; however, the infiltration of intratumoral neutrophils in colorectal carcinoma (CRC) and its effect on CRC patients' prognosis are poorly understood. Methodology/Principal Findings In this study, the methods of tissue microarray and immunohistochemistry (IHC) were used to investigate the prognostic significance of intratumoral CD66b+ neutrophil in CRC. According to receiver operating characteristic curve analysis, the cutoff score for high intratumoral CD66b+ neutrophil in CRC was defined when the mean counts were more than 60 per TMA spot. In our study, high intratumoral CD66b+ neutrophil was observed in 104/229 (45.4%) of CRCs and in 29/229 (12.7%) of adjacent mucosal tissues. Further correlation analysis showed that high intratumoral neutrophil was positively correlated with pT status, pM status and clinical stage (P<0.05). In univariate survival analysis, a significant association between high intratumoral neutrophil and shortened patients' survival was found (P<0.0001). In different subsets of CRC patients, intratumoral neutrophil was also a prognostic indicator in patients with stage II, stage III, grade 2, grade 3, pT1, pT2, pN0 and pN1 (P<0.05). Importantly, high intratumoral neutrophil was evaluated as an independent prognostic factor in multivariate analysis (P<0.05). Conclusions/Significance Our results provide evidence that increased intratumoral neutrophil in CRC may be important in the acquisition of a malignant phenotype, indicating that the presence of intratumoral neutrophil is an independent factor for poor prognosis of patients with CRC.

[1]  H. Møller,et al.  Intratumoral neutrophils and plasmacytoid dendritic cells indicate poor prognosis and are associated with pSTAT3 expression in AJCC stage I/II melanoma , 2012, Cancer.

[2]  P. Hofman,et al.  Predictive clinical outcome of the intratumoral CD66b‐positive neutrophil‐to‐CD8‐positive T‐cell ratio in patients with resectable nonsmall cell lung cancer , 2012, Cancer.

[3]  X. Bian,et al.  Overexpression of EIF5A2 promotes colorectal carcinoma cell aggressiveness by upregulating MTA1 through C-myc to induce epithelial–mesenchymaltransition , 2011, Gut.

[4]  Wei Zhang,et al.  NGAL Expression Is Elevated in Both Colorectal Adenoma–Carcinoma Sequence and Cancer Progression and Enhances Tumorigenesis in Xenograft Mouse Models , 2011, Clinical Cancer Research.

[5]  Xiao‐Yu Yin,et al.  Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma. , 2011, Journal of hepatology.

[6]  V. Baracos,et al.  Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer , 2011, British Journal of Cancer.

[7]  S. Qiu,et al.  Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection. , 2011, Journal of hepatology.

[8]  Y. Zeng,et al.  EZH2 protein: a promising immunomarker for the detection of hepatocellular carcinomas in liver needle biopsies , 2011, Gut.

[9]  E. El-Omar,et al.  The Inflammatory Microenvironment in Colorectal Neoplasia , 2011, PloS one.

[10]  Bin Zhang,et al.  Decreased expression of PinX1 protein is correlated with tumor development and is a new independent poor prognostic factor in ovarian carcinoma , 2010, Cancer science.

[11]  N. Marcussen,et al.  Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  A. Mantovani The yin-yang of tumor-associated neutrophils. , 2009, Cancer cell.

[13]  G. Cheng,et al.  Polarization of tumor-associated neutrophil phenotype by TGF-beta: "N1" versus "N2" TAN. , 2009, Cancer cell.

[14]  I. Shmulevich,et al.  NGAL decreases E-cadherin-mediated cell-cell adhesion and increases cell motility and invasion through Rac1 in colon carcinoma cells , 2009, Laboratory Investigation.

[15]  A. Karameris,et al.  Prognostic significance of VEGF expression evaluated by quantitative immunohistochemical analysis in colorectal cancer. , 2008, The Journal of surgical research.

[16]  Mallika Singh,et al.  Role of Bv8 in neutrophil-dependent angiogenesis in a transgenic model of cancer progression , 2008, Proceedings of the National Academy of Sciences.

[17]  M. Luciani,et al.  Activated neutrophils induce an hMSH2-dependent G2/M checkpoint arrest and replication errors at a (CA)13-repeat in colon epithelial cells , 2008, Gut.

[18]  R. Jalan,et al.  Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome , 2007, Hepatology.

[19]  Z. Trajanoski,et al.  Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome , 2006, Science.

[20]  Carl Nathan,et al.  Neutrophils and immunity: challenges and opportunities , 2006, Nature Reviews Immunology.

[21]  John Condeelis,et al.  Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis , 2006, Cell.

[22]  C. Ko,et al.  Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging. , 2005, Journal of the National Cancer Institute.

[23]  J. Kleinjans,et al.  Neutrophil-mediated formation of carcinogenic N-nitroso compounds in an in vitro model for intestinal inflammation. , 2004, Toxicology letters.

[24]  Zhifu Sun,et al.  Role of imbalance between neutrophil elastase and alpha 1-antitrypsin in cancer development and progression. , 2004, The Lancet. Oncology.

[25]  H. Müller-Hermelink,et al.  Pleiotropic effects of CXC chemokines in gastric carcinoma: differences in CXCL8 and CXCL1 expression between diffuse and intestinal types of gastric carcinoma , 2003, Clinical and experimental immunology.

[26]  D. Hanahan,et al.  MMP-9 Supplied by Bone Marrow–Derived Cells Contributes to Skin Carcinogenesis , 2000, Cell.

[27]  H. Nielsen,et al.  Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue , 1999, The Journal of pathology.

[28]  D. Obrand,et al.  Incidence and patterns of recurrence following curative resection for colorectal carcinoma , 1997, Diseases of the colon and rectum.

[29]  Tamaki Yamada,et al.  Neutrophil-mediated nitrosamine formation: role of nitric oxide in rats. , 1992, Gastroenterology.

[30]  A. Mantovani,et al.  Cancer: Inflaming metastasis , 2008, Nature.

[31]  P. Rosenberg,et al.  Rapid increase in colorectal cancer rates in urban Shanghai, 1972-97, in relation to dietary changes. , 2002, Journal of cancer epidemiology and prevention.